Research provides new insights into molecular “crosstalk” in pancreas cancer cells, identifying vulnerabilities that could provide a target for therapeutic drugs already being studied in several cancers.
“Pancreatic ductal adenocarcinoma, which is highly resistant to current therapies, is expected to become the second most common cause of cancer-related deaths in the United States within this decade,” said the senior author. “Results of this study increase our understanding of the inflammatory microenvironment within these tumors and suggest targeted pharmacological strategies that could be employed to leverage this hallmark feature of pancreas cancer by current treatments.”
The preclinical research, using tumor cells from patients and cell line-derived xenograft tumors, was published in Cell Reports. It centers on STING-driven type I interferon, an immune system signaling molecule that impairs cancer cell proliferation in lab studies but tends to have the opposite effect in clinical practice, where tumor cells adapt to them and often become resistant to treatment with radiation, chemotherapy and immune checkpoint blockade. Interferons are produced in immune and other cells, including some types of cancer cells.
“We determined that a subset of PDAC tumors exhibit an intrinsic interferon response that has not been modeled by standard cell culture conditions. Using several advanced techniques, we found that interferon signaling causes the tumor cells to rely on a specific signaling pathway for survival. However, if we inhibit a protein called ATR, which plays an important role in this signaling pathway, we can cause catastrophic damage to the cancer cells’ DNA and induce programmed cell death,” said a co-first author of the article.
Results suggest that new small molecule drugs that inhibit ATR and are being studied for treatment of several cancers, including PDAC, could be used in combination with interferon “amplification” to thwart the tumor cells’ ability to escape.
The researchers defined a series of molecular interactions leading to a cascade of intracellular events. Through its influence on several genes, interferon alters the metabolic processes supporting the foundation of the cancer cells’ DNA, reducing the supply of biochemical building blocks needed for the DNA to survive. To compensate, the cancer cells rely on a signaling pathway – the replication stress response signaling pathway – that can enable threatened DNA to survive, largely through the influence of ATR.
The author said one potential intervention deserving further exploration, according to results of the study, therapy that activates another signaling pathway, called STING.
“STING activation induces interferon signaling in PDAC cells and triggers ATR activation,” the author said. “This strategy would enhance the attack brought about through interferon signaling while preventing escape through the collateral pathway by shutting it down with ATR-inhibiting drugs.”
https://www.cell.com/cell-reports/fulltext/S2211-1247(21)01745-9
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Freprogramming-of&filter=22
A cross talk between IFN, DNA replication stress response networks, and nucleotide metabolism in pancreatic cancer cells
- 1,376 views
- Added
Latest News
More influence of environme…
By newseditor
Posted 24 Apr
The assembly of the human c…
By newseditor
Posted 24 Apr
Wiring of the human neocortex
By newseditor
Posted 24 Apr
Abusive drugs hijack natura…
By newseditor
Posted 23 Apr
Mechanism of action of the…
By newseditor
Posted 23 Apr
Other Top Stories
Facioscapulohumeral muscular dystrophy (FSHD) mouse model developed!
Read more
How eyes get clogged in glaucoma
Read more
Animal model for bipolar disorder?
Read more
Converting bad body fat into good fat
Read more
Key regulator of male fertility identified!
Read more
Protocols
A programmable targeted pro…
By newseditor
Posted 23 Apr
MemPrep, a new technology f…
By newseditor
Posted 08 Apr
A tangible method to assess…
By newseditor
Posted 08 Apr
Stem cell-derived vessels-o…
By newseditor
Posted 06 Apr
Single-cell biclustering fo…
By newseditor
Posted 01 Apr
Publications
Distinct genetic and enviro…
By newseditor
Posted 24 Apr
Hippocampus-to-amygdala pat…
By newseditor
Posted 24 Apr
Integrative spatial analysi…
By newseditor
Posted 24 Apr
Time-series reconstruction…
By newseditor
Posted 24 Apr
Harnessing gastrointestinal…
By newseditor
Posted 24 Apr
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar